Antifolate agents, such as methotrexate, have been used as antitumor agents for many years and in 1954 metoprine (compound of formula I where R.sup.1 .dbd.Cl, R.sup.2 .dbd.Cl, R.sup.3 .dbd.Me) entered clinical trials. ##STR3##
Although severe toxicity associated with this agent precluded further evaluation, the use of pyrimethamine (I, R.sup.1 .dbd.Cl R.sup.2 .dbd.H R.sup.3 .dbd.Et) has been explored and diaminopyrimidine compounds have also been developed which have inherent species selectivity as antibacterial and antimalarial agents.
Compounds have now been developed with inhibition of dihydrofolate reductase comparable to or greater than metoprine but which are relatively less toxic. These compounds are of interest as antiproliferative agents useful in the treatment of tumors, psoriasis, bacterial, malarial and trypanosomal infections.
Certain of such compounds are, however, disclosed as intermediates in an International Application (Published under No. WO84/04746) which relates to azido-substituted pyrimidine derivatives.